Grove Jane I, Stephens Camilla, Lucena M Isabel, Andrade Raúl J, Weber Sabine, Gerbes Alexander, Bjornsson Einar S, Stirnimann Guido, Daly Ann K, Hackl Matthias, Khamina-Kotisch Kseniya, Marin Jose J G, Monte Maria J, Paciga Sara A, Lingaya Melanie, Forootan Shiva S, Goldring Christopher E P, Poetz Oliver, Lombaard Rudolf, Stege Alexandra, Bjorrnsson Helgi K, Robles-Diaz Mercedes, Li Dingzhou, Tran Thi Dong Binh, Ramaiah Shashi K, Samodelov Sophia L, Kullak-Ublick Gerd A, Aithal Guruprasad P
Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK.
NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.
Diagn Progn Res. 2023 Sep 12;7(1):18. doi: 10.1186/s41512-023-00155-z.
A lack of biomarkers that detect drug-induced liver injury (DILI) accurately continues to hinder early- and late-stage drug development and remains a challenge in clinical practice. The Innovative Medicines Initiative's TransBioLine consortium comprising academic and industry partners is developing a prospective repository of deeply phenotyped cases and controls with biological samples during liver injury progression to facilitate biomarker discovery, evaluation, validation and qualification.In a nested case-control design, patients who meet one of these criteria, alanine transaminase (ALT) ≥ 5 × the upper limit of normal (ULN), alkaline phosphatase ≥ 2 × ULN or ALT ≥ 3 ULN with total bilirubin > 2 × ULN, are enrolled. After completed clinical investigations, Roussel Uclaf Causality Assessment and expert panel review are used to adjudicate episodes as DILI or alternative liver diseases (acute non-DILI controls). Two blood samples are taken: at recruitment and follow-up. Sample size is as follows: 300 cases of DILI and 130 acute non-DILI controls. Additional cross-sectional cohorts (1 visit) are as follows: Healthy volunteers (n = 120), controls with chronic alcohol-related or non-alcoholic fatty liver disease (n = 100 each) and patients with psoriasis or rheumatoid arthritis (n = 100, 50 treated with methotrexate) are enrolled. Candidate biomarkers prioritised for evaluation include osteopontin, glutamate dehydrogenase, cytokeratin-18 (full length and caspase cleaved), macrophage-colony-stimulating factor 1 receptor and high mobility group protein B1 as well as bile acids, sphingolipids and microRNAs. The TransBioLine project is enabling biomarker discovery and validation that could improve detection, diagnostic accuracy and prognostication of DILI in premarketing clinical trials and for clinical healthcare application.
缺乏能够准确检测药物性肝损伤（DILI）的生物标志物，这持续阻碍着药物研发的早期和后期阶段，并且在临床实践中仍然是一项挑战。由学术和行业合作伙伴组成的创新药物倡议组织的跨生物线联盟，正在建立一个前瞻性储存库，其中包含在肝损伤进展过程中具有生物样本的深度表型病例和对照，以促进生物标志物的发现、评估、验证和鉴定。
在一项巢式病例对照设计中，符合以下标准之一的患者被纳入研究：丙氨酸转氨酶（ALT）≥5倍正常上限（ULN）、碱性磷酸酶≥2倍ULN或ALT≥3 ULN且总胆红素>2倍ULN。完成临床研究后，使用鲁塞尔·优克福因果关系评估和专家小组审查来判定这些病例为药物性肝损伤或其他肝病（急性非药物性肝损伤对照）。采集两份血液样本：在招募时和随访时。样本量如下：300例药物性肝损伤病例和130例急性非药物性肝损伤对照。另外的横断面队列（单次就诊）如下：纳入健康志愿者（n = 120）、患有慢性酒精性或非酒精性脂肪性肝病的对照（各n = 100）以及银屑病或类风湿关节炎患者（n = 100，其中50例接受甲氨蝶呤治疗）。优先评估的候选生物标志物包括骨桥蛋白、谷氨酸脱氢酶、细胞角蛋白18（全长和半胱天冬酶切割片段）、巨噬细胞集落刺激因子1受体、高迁移率族蛋白B1以及胆汁酸、鞘脂和微小RNA。跨生物线项目正在推动生物标志物的发现和验证，这可能会改善上市前临床试验以及临床医疗应用中药物性肝损伤的检测、诊断准确性和预后评估。
